Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Ranjan, Amaresh K.; Zhang, Zhong; Briyal, Seema; Gulati, Anil

doi:10.3389/fphar.2021.616253

Cited by 10 publications

(6 citation statements)

References 53 publications

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“…Analysis of kidney tissues in these rats showed significant up-regulation ( p = 0.024) of hypoxia-inducible factor 1a (HIF-1α) and reduced ( p = 0.03) mitochondrial DNA damage than control rats. We also observed reduced acute kidney injury and apoptosis in kidneys in CQ rats ( Ranjan et al, 2020 ; Ranjan et al, 2021 ). Thus, CQ, known to activate the α-adrenergic system, has proven to be an effective resuscitative agent for hypovolemic/hemorrhagic shock and potentially improves cardiovascular function, renal tissue perfusion, and protection.…”

Section: Development Of Centhaquine An α-2 Agonist As a Resuscitative...supporting

confidence: 53%

Role of adrenergic receptors in shock

Geevarghese¹,

Patel

Gulati

et al. 2023

Front. Physiol.

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Shock is a severe, life-threatening medical condition with a high mortality rate worldwide. All four major categories of shock (along with their various subtypes)—hypovolemic, distributive, cardiogenic, and obstructive, involve a dramatic mismatch between oxygen supply and demand, and share standard features of decreased cardiac output, reduced blood pressure, and overall hypoperfusion. Immediate and appropriate intervention is required regardless of shock type, as a delay can result in cellular dysfunction, irreversible multiple organ failure, and death. Studies have shown that dysfunction and downregulation of adrenergic receptors (ARs) are often implicated in these shock conditions; for example, their density is shown to be decreased in hypovolemic and cardiogenic shock, while their reduced signaling in the brain and vasculature decrease blood perfusion and oxygen supply. There are two main categories of ARs, α, and β, each with its subtypes and distributions. Our group has demonstrated that a dose of .02 mg/kg body wt of centhaquine (CQ) specifically activates α2B ARs on venous circulation along with the central α2A ARs after hypovolemic/hemorrhagic shock. Activating these receptors by CQ increases cardiac output (CO) and reduces systemic vascular resistance (SVR), with a net increase in blood pressure and tissue perfusion. The clinical trials of CQ conducted by Pharmazz Inc. in India have demonstrated significantly improved survival in shock patients. CQ improved blood pressure and shock index, indicating better blood circulation, and reduced lactate levels in the blood compared to in-use standard resuscitative agents. After successful clinical trials, CQ is being marketed as a drug (Lyfaquin®) for hypovolemic/hemorrhagic shock in India, and United States FDA has approved the phase III IND application. It is anticipated that the phase III trial in the United States will begin in 2023. Thus, we have demonstrated that α2 ARs could be suitable targets for treating or managing hypovolemic/hemorrhagic shock. Further understanding of ARs in shock would help find new potential pharmacological targets.

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Section: Development Of Centhaquine An α-2 Agonist As a Resuscitative...supporting

confidence: 53%

Role of adrenergic receptors in shock

Geevarghese¹,

Patel

Gulati

et al. 2023

Front. Physiol.

Self Cite

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“…Moreover, analysis of kidney tissues in these rats showed significant up-regulation (p=0.024) of hypoxia inducible factor 1 (HIF-1). We also observed down-regulation of early acute kidney injury and apoptotic markers after resuscitation with CQ [152,153]. Overall, these results showed that CQ is as an effective resuscitative agent with potential to improve cardiovascular function as well as renal tissue perfusion and protection after hemorrhagic shock.…”

Section: Regulation Of Blood Pressure After Hemorrhagic Shocksupporting

confidence: 58%

Controls of Central and Peripheral Blood Pressure and Hemorrhagic/Hypovolemic Shock

Ranjan¹,

Gulati²

2022

Preprint

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The pressure exerted on the heart and blood vessels because of blood flow is considered as an important parameter for the cardiovascular function. It determines sufficient blood perfusion as well as transportation of nutrition, oxygen and other essential factors to every organ. Pressure in the primary arteries located near the heart and the brain, known as central blood pressure (CBP), while in peripheral arteries, known as peripheral blood pressure (PBP). Normally, CBP and PBP are correlated; however, cardiovascular disorders interfere their regulation and affect the blood flow in vital organs and accessory organs, differently. Therefore, understanding each of them in normal and disease conditions is essential for managing various cardiovascular disorders and increasing their treatment outcomes. In this review, we have described the control systems (neural, hormonal, osmotic and cellular) of the blood pressure and its regulation in hypovolemic shock using centhaquine (Lyfaquin®) as a resuscitative agent.

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“…Considering that venous endothelial cells are less thrombogenic than arterial endothelial cells [ 47 ], centhaquine, as a pure venoconstrictor (α2B-adrenoreceptors), may maintain a steady flow and no or minimal pulsatility in veins [ 48 , 49 ], thus exploiting the beneficial anti-thrombogenic profile of venous endothelial cells [ 47 ] without directly affecting the arterial side of the circulation [ 41 ]. Moreover, its action on central α2A-adrenoreceptors facilitates arteriolar flow and tissue perfusion, which enhances organ protection during severe hemorrhage [ 50 , 51 ]. Further research is necessary to fully clarify the effects of centhaquine at the molecular and cellular level and, ultimately, its integrative mechanism of action.…”

Section: Discussionmentioning

confidence: 99%

Effect of Centhaquine on the Coagulation Cascade in Normal State and Uncontrolled Hemorrhage: A Multiphase Study Combining Ex Vivo and In Vivo Experiments in Different Species

Chalkias,

Pais,

Gulati

2024

IJMS

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Centhaquine is a novel vasopressor acting on α2A- and α2B-adrenoreceptors, increasing venous return and improving tissue perfusion. We investigated the effects of centhaquine on blood coagulation in normal state and uncontrolled hemorrhage using ex vivo and in vivo experiments in different species. Thromboelastography (TEG) parameters included clotting time (R), clot kinetics [K and angle (α)], clot strength (MA), and percent lysis 30 min post-MA (LY30). In normal rat blood, centhaquine did not alter R, K, α, MA, or LY30 values of the normal vehicle group or the antithrombotic effects of aspirin and heparin. Subsequently, New Zealand white rabbits with uncontrolled hemorrhage were assigned to three resuscitation groups: Sal-MAP 45 group (normal saline to maintain a mean arterial pressure, MAP, of 45 mmHg), Centh-MAP 45 group (0.05 mg kg−1 centhaquine plus normal saline to maintain a MAP of 45 mmHg), and Sal-MAP 60 group (normal saline to maintain a MAP of 60 mmHg). The Sal-MAP 45 group was characterized by no change in R, reduced K and MA, and increased α. In the Centh-MAP 45 group, TEG showed no change in R, K, and α compared to saline; however, MA increased significantly (p = 0.018). In the Sal-MAP 60 group, TEG showed no change in R, an increase in α (p < 0.001), a decrease in K (p < 0.01), and a decrease in MA (p = 0.029) compared to the Centh-MAP 45 group. In conclusion, centhaquine does not impair coagulation and facilitates hemostatic resuscitation.

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Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Cited by 10 publications

References 53 publications

Role of adrenergic receptors in shock

Role of adrenergic receptors in shock

Controls of Central and Peripheral Blood Pressure and Hemorrhagic/Hypovolemic Shock

Effect of Centhaquine on the Coagulation Cascade in Normal State and Uncontrolled Hemorrhage: A Multiphase Study Combining Ex Vivo and In Vivo Experiments in Different Species

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